Paradoxical skin lesions induced by IL-17 inhibitors in SAPHO syndrome

Dear Editor,

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare autoinflammatory disorder disease characterized by skin lesions and osteoarticular involvement. Currently, no consensus has been reached regarding the treatment of SAPHO syndrome, and there is no standardized therapy. Patients with SAPHO syndrome who do not respond to conventional treatment are often considered for the use of biologic agents, such as TNF blockers. For patients who do not respond to TNF blockers, biologics targeting the IL-17/IL-23 axis could be used (1). Research suggests that IL-17 blockade therapy may be effective in treating skin disease (2). However, biologic agents may trigger paradoxical skin lesions and it may even induce paradoxical psoriasiform cutaneous eruptions.

We reported 7 cases of paradoxical skin lesions in SAPHO syndrome patients treated with IL-17A inhibitors. The demographic data and clinical information of the 7 patients are listed (Table 1). Before treatment with IL-17A inhibitors, all patients had PPP. All patients developed paradoxical psoriasis within 4 weeks of receiving IL-17A inhibitor treatment. After using IL-17A inhibitors, joint pain symptoms improved in 3 patients. One patients developed new sterile pimples in other parts of their bodies. The paradoxical skin lesions presented in various forms, including sterile pustules, alopecia areata and nail damage. All patients experienced significant relief of the paradoxical psoriasis within 12 weeks after discontinuing IL-17 inhibitors and taking oral tofacitinib (Figure 1). The occurrence of these paradoxical psoriasis are believed to be related to the use of IL-17A inhibitors.

Figure 1. (A–G) The paradoxical skin lesions of the 7 cases with SAPHO syndrome treated with IL-17A inhibitors. (Ai) After discontinuing IL-17A inhibitors and adding tofacitinib for 10 weeks, the paradoxical skin lesions has improved. (Bi) After discontinuing IL-17A inhibitors and adding tofacitinib for 2 weeks, the paradoxical skin lesions has improved. (Ci) After discontinuing IL-17A inhibitors and adding tofacitinib for 2 weeks, the paradoxical skin lesions has improved. (Di) After discontinuing IL-17A inhibitors and adding tofacitinib for 12 weeks, the paradoxical skin lesions has improved. (Ei) After discontinuing IL-17A inhibitors and adding tofacitinib for 8 weeks, the paradoxical skin lesions has improved. (Fi) After discontinuing IL-17A inhibitors and adding tofacitinib for 5 weeks, the paradoxical skin lesions has improved. (Gi) After discontinuing IL-17A inhibitors and adding tofacitinib for 6 weeks, the paradoxical skin lesions has improved.

Table 1. Patient and skin eruption characteristics.

Pt	Sex	Age(yrs)	Anti-IL17A agent	Duration of therapy (weeks)	Joint pain symptoms improved	PPP improved	Clinical aspects	Discontinuation of treatment	Management	Time to remisssion (weeks)
1	F	39	Secukinumab	2	No	No	PPP aggravated, nail damage.	Yes	Tofacitinib	10
2	M	58	Secukinumab	4	Yes	No	Sterile pimples eruption.	Yes	Tofacitinib	2
3	F	54	Secukinumab	3	No	No	Sterile pimples eruption.	Yes	Tofacitinib	2
4	M	43	Secukinumab	3	No	No	PPP aggravated.	Yes	Tofacitinib	12
5	M	50	Secukinumab	4	Yes	No	PPP aggravated.	Yes	Tofacitinib	8
6	F	31	Secukinumab	2	Yes	No	PPP aggravated, alopecia areata.	Yes	Tofacitinib	5
7	F	37	Secukinumab	4	No	No	PPP aggravated, new developed sterile pimples.	Yes	Tofacitinib	6

F: female; M: male; PPP: Palmarplantar pustulosis.

IL-17 is a key cytokine involved in the relevant immune pathways of cutaneous and osteoarticular inflammation in SAPHO syndrome. In the joints, cytokines such as IL-17A and IL-17F are produced by T-cell subsets such as TH17, which promote bone erosion and cartilage destruction.In the skin, activation of keratinocytes by IL-23 and IL-17A lead to the inflammatory process (1). The induction of paradoxical psoriasis by biologic agents such as TNF blockers has been widely reported. Some case reports suggest that IL-17A inhibitors can also induce paradoxical psoriasis. We report a series of cases involving 7 patients who experienced paradoxical psoriasis while being treated with IL-17A inhibitors (secukinumab or ixekizumab) for SAPHO syndrome.

The pathological mechanism of paradoxical skin lesions is not yet clear. The use of IL-17 inhibitors may cause defects in dendritic cell maturation by affecting TNF-α levels, ultimately leading to sustained production of IFN-α (3). The occurrence of paradoxical skin reactions may be associated with increased upstream cytokines such as IL-23 due to the blockade of IL-17A (4). Inhibition of IL-17A by secukinumab and ixekizumab can lead to compensatory increases in other IL-17 subtypes such as IL-17C (5). IL-17 inhibitors can disrupt the gut and skin microbiota and cause pathogenic bacterial infections. The interaction between the gut and skin microbiota and the immune system may be a new pathogenic mechanism of paradoxical psoriasis triggered by IL-17 inhibitors (6).

Early identification and treatment of paradoxical psoriasis are crucial in dermatology. Dermatologists should be vigilant for the development of paradoxical psoriasis in patients on IL-17 antagonists. Patients experiencing paradoxical psoriasis to biologics may consider using treatment principles that do not induce paradoxical psoriasis, such as Janus kinase inhibitors (7). Recent studies revealed that Janus kinase inhibitors can directly or indirectly block the action of multiple cytokines, including IL-17 and IL-23 (8). The 7 reported cases were all treated with tofacitinib for paradoxical psoriasis caused by IL-17A inhibitors, and the paradoxical psoriasis was effectively controlled.

Authors contributions

Chen Li and Xiujuan Hou designed this study. Yuan Li and Fanzhang Meng wrote the manuscript. Haixu Jiang,Qiuwei Peng and Dan Yin was responsible for data collection. All authors approved the final manuscript. Yuan Li and Fanzhang Meng contributed equally to this work.

Ethical approval

This work was approved by the medical ethics committee of Fangshan Hospital of Beijing University of Chinese Medicine with the following reference numbers: FZJ JS-2021-002.

Consent to participate

Informed consent was obtained from the patient.

Consent to publication

Informed consent to publication was obtained from the patient.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets analyzed for this study are available from the corresponding author Dr. Chen Li ([email protected]) upon reasonable request.

Additional information

Funding

The study was supported by the National Natural Science Foundation of China (grant no. 82074246) and the Fundamental Research Fundsfor the Central Universities (grant no. 2023‐JYB‐JBZD‐008)